Investigating the role of the miR-125b target ARID3A in the pathology of myeloid leukemia associated with Down syndrome

• Applicants: Professor Dr. Dirk Heckl; Professor Dr. Jan-Henning Cornelius Klusmann
• Subject Area: Hematology, Oncology ; Pediatric and Adolescent Medicine
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 453925335

Down syndrome-associated myeloid leukemia (ML-DS) is characterized by the triad of trisomy 21, fetal origin and mutations in GATA1 (GATA1s mutations). We previously found that members of the miR-99a~125b tricistron (miR-125b-2, miR-99a and let-7c) on chromosome 21 are overexpressed in ML-DS. However, the synergy between miR-99a~125b overexpression and GATA1s in disease initiation and progression remains unclear. Using a fluorescence-based lentiviral barcoding system to map genetic interactions in gene-edited fetal hematopoietic stem/progenitor cells from the liver (FLCs), we observed that the combination of Gata1s and miR-125b synergized to increase the proliferation of immature megakaryocytic progenitor cells in vitro and promote leukemogenesis in vivo. Other members of the miR-99a~125b tricistron did not induce such effects either alone or in combination. Integrative analysis of shRNA-based positive selection screening data and gene expression changes upon switching miR-125b on and off in Gata1s-FLCs suggested Arid3a as the main target of miR-125b that drives its synergy with Gata1s. ARID3a (AT-Rich Interaction Domain 3A; alias: Bright) is a transcription factor that has been implicated in the control of a variety of processes, including embryonic development and early hematopoiesis. The aim of this project is to understand the function of ARID3a in fetal hematopoiesis and delineate its role in the pathogenesis of human myeloid leukemia – particularly its synergy with Gata1s in TAM and ML-DS. This goal is to be achieved by (1) establishing Arid3a as a direct target of miR-125b and a cooperating partner of Gata1s in leukemogenesis, (2) investigating the role of ARID3A in normal and malignant hematopoietic cells in vitro and in vivo and (3) uncovering the molecular function and interaction network of ARID3A with state-of-the-art technologies. Our newly developed murine Gata1s preleukemic model, together with our patient-derived xenograft (PDX) bank, offer us new, previously unprecedented avenues to achieving this goal. Using these resources, we will be able to contribute a decisive step towards understanding the epistatic coordination of hematopoiesis and oncogenesis through interactions between protein-coding and non-coding genes.

• DFG Programme: Research Grants